It is becoming increasingly clear that HAART alone is unlikely to clear HIV infection and must be combined with alternate forms of therapy to decrease a lifetime dependence on the drugs, which are associated with significant side effects and the increasing potential of drug resistance. Our lab has focused its efforts on devising and testing immune based strategies using select recombinant rhesus macaque immune enhancing cytokines. Most cytokines with potential for expanding and augmenting cellular immune functions often also have the potential for enhancing viral replication and augmenting viral loads. These facts underscore a need for a careful evaluation of such immune based therapies in animal models prior to their use in HTV infected humans. Our lab has already shown that rMamu-El2 administered in an optimized dose schedule to rhesus macaques during acute infection with highly pathogenic SIVmac251 led to lower viral replication, lower pro-viral loads and markedly prolonged disease free survival. This study provided proof of concept that SIV pathogenicity can be successfully countered by efficient antiviral immune responses. This proposal will exploit these findings by exploring strategies to improve antiviral control by combining the IL-12 treatment with STI based chemotherapy post infection in efforts to provide clinically relevant data (Aim #1). Current data from our studies clearly suggest that the enhanced long-term antiviral immune responses are by and large dependant upon the presence of a functional CD4' T cell pool. In Aim #2, we therefore propose to evaluate strategies to further expand and maintain such cell lineages by combining the STILL-12 therapy with the addition of rMamu-IL2 and rMamu-IL15, two factors known to differentially regulate the expansion and longevity of memory T cells in vivo. Armed with the data on the pharmacokinetics and biologically effective in vivo doses of these select rMamu cytokines and assays such as ELISPOT/ICC against sets of overlapping peptides that cover the entire sequences of SIV gag, env, tat, vif and nef proteins, our lab is poised to define the mechanisms by which such immune based therapies in concert with chemotherapy, induce their potential disease protective effects.